We focus on drugs targeting the genome, especially novel topoisomerase inhibitors as single agents and in combination with DNA repair and immune checkpoint inhibitors. One of our topoisomerase I (TOP1) inhibitors, LMP400 (Indotecan) finished Phase 1 clinical trials. Another (LMP776, Indimitecan) is finishing phase 1 and LMP744 is in phase 1. We have clinical trials with tumor-targeted TOP1 inhibitors (Onivyde, CRLX101, PLX-038 and PEN-866), and clinical trials with combination of TOP1 inhibitors with poly(ADPribose)polymerase (PARP1/2) and immune checkpoint inhibitors. Our ongoing clinical trials include: (NCI protocol #PITrial nameCancer Phase) 15-c-0150, Thomas, ATR inhibitor plus topotecan, Small cell lung cancer and extrapulmonary cancer, Phase II; 16-c-0107, Thomas, Nanoparticle campto plus olaparib, small cell lung cancer, prostate cancer, bladder cancer, Phase II; 17-c-0012, Thomas, Liposomal irinotecan plus veliparib, solid tumors, Phase I; 17-C-0117, Thomas, Hsp90-SN39 conjugate, Solid tumors, Phase I; 15-c-1045, Lee, Durvalumab plus olaparib, small cell lung cancer, Phase II; 18-C-0110, Thomas, PD-L1/TGFB antibody plus temozolomide, small cell lung cancer, Phase II. The clinical trials openings in 2019 include: (TrialCancerPhase) PEG-SN38 plus rucaparib, solid tumors, Phase I; LMP400 plus olaparib HRD, solid tumors, Phase I; Durvalumab plus olaparib, EGFR-transformed small cell lung cancer, Phase II; ATR inhibitor plus topotecan, small cell lung cancer and extrapulmonary cancers, Randomized Phase II.